The field of the invention is treatment of viral infections.
Many viral infections are associated with a shift in the cytokine profile from a TH1 response to Th2 response, and recent research suggests that a control over the balance between the TH1 response and the Th2 response might be advantageous in terms of generation and/or maintenance of immunity against viral infection. An increased TH1 response appears to be especially important in HIV infection, where long-term survivors exhibit a TH1 dominated response, while progressors have a more Th2 dominated response. For example, Barker et al. suggest that disease progression in HIV results from a shift in cytokine production within the infected host from a TH1 to a Th2 pattern [Barker E, Mackewicz C E, Levy J A Proc Natl Acad Sci USA 1995 November 21;92(24):11135-9]. Similarly, a decrease in the Th2 response appears to be of therapeutic significance, since Reiser et al. report that Th2 cytokine levels are elevated in chronic hepatitis C virus infection [Reiser, M. et al.; J Hepatol 1997 March;26(3):471-8]. Various methods of influencing the TH1/Th2 balance are known, and may broadly be categorized in cytokine-related methods and non-cytokine related methods.
In cytokine related methods of treatment, cytokines are administered to modulate the TH1/Th2 balance towards either a TH1-type response or a Th2-type response. For example, Knight et al. postulate that treatment with IL-12 (Interleukine-12), a cytokine that promotes the development of TH1 cells, may be used as a treatment for AIDS since IL-12 administration has been shown to be effective at restoring cell-mediated immunity in mice infected with mouse AIDS virus or with Rauscher Leukemia Virus (RLV) [Knight, S. C. and Patterson, S., Annu. Rev. Immunol. 1994. 15: 593-615]. In another example, Gracie, J A. et al., demonstrated that administration of IL-18 to mice exhibited pleiotropic activities critical to the development of TH1 responses. [Gracie et al. J Clin Invest 1999 November 15;104(10):1393-1401]. Although the administration of cytokines typically results in relatively specific increases in desired TH1 cytokines, prolonged administration of cytokines may be problematic for various reasons. For example, the production of recombinant cytokines is relatively expensive, and isolation of non-recombinant cytokines from natural sources is generally difficult due to the very low concentration of cytokines in natural sources. A further problem is that cytokine preparations typically need to have a very high degree of purity in order to avoid allergic reactions upon repeated administration. Moreover, depending on the nature of the cytokine, cytokines may not be well tolerated in patients.
In a non-cytokine related method, immuno-modulatory substances other than cytokines are employed to modulate the balance between a TH1 response and a Th2 response. For example, Sprietsma J. E. suggests [Sprietsma J. E; Med Hypotheses 1999 July;53(1):6-16] that zinc ions (Zn++) and nitric oxide (NO), together with glutathione (GSH) and its oxidized form, GSSG, may help to regulate an immune response to antigens. The author reports in more detail that deficiencies of Zn++, NO and/or GSH shift the TH1/Th2 balance towards Th2, and that replenishment with Zn++, NO and/or GSH may shift the TH1/Th2 balance towards TH1. Administration of Zn++ or GSH/GSSG is especially advantageous, since these substances are non-toxic at even elevated concentrations, and inexpensive to produce. Furthermore, Zn++ and GSH/GSSG preparations may be orally administered, and therefore significantly reduce the risk of allergic reactions, especially when the preparations are not ultrapure. However, the administration of Zn++ and/or GSH/GSSG seems to be beneficial only to restore a Th1/Th2 balance from a Th2 dominated state, whereas it is unclear if administration of Zn++ and/or GSH/GSSG may increase a TH1 response from a normal TH1/Th2 balance.
In another example, U.S. Pat. No. 6,150,337 incorporated herein by reference, a method is described in which the inventors employ the nucleoside analog Ribavirin (1-(5-Deoxy-xcex2-D-ribo-furanosyl)-1,2,4-triazole-3-carboxamide) to modulate the balance of the TH1/Th2 response. The use of Ribavirin is especially advantageous for the treatment of viral infections, because Ribavirin not only modulates the immune response towards a TH1 response, but also acts as an inhibitory agent for viral replication. For example, Ribavirin has been successfully used in the treatment of Hepatitis C. Some of this effect has been attributed to antiviral effects and some of this effect has been attributed to the cytokine balance.
Although Ribavirin showed a desirable effect in virus count and immune status, prolonged administration of Ribavirin at relatively high doses was frequently associated with several side effects, including leukopenia and hemolytic anemia. In order to reduce the occurrence or severity of side effects, co-administration of Ribavirin with IFNxcex1-2B has been introduced [Reichert, O., et al.1998; Lancet 351:83-87]. However, the co-administration of Ribavirin with IFNxcex1-2B increases the cost of treatment significantly. Moreover, prolonged administration of IFNxcex1-2B increases the risk of new side effects attributable to IFNxcex1-2B.
Despite the relatively successful administration of Ribavirin in the treatment of viral diseases, the use of Ribavirin remains problematic due to the generation of various side effects. Therefore, there is a need to provide improved methods and compositions to modulate the TH1/Th2 balance at a relatively low or no toxic side effects for treatment of viral infections.
The present invention is directed to a method of treatment of a viral infection in a patient, in which Levovirin(trademark) (1-(xcex2-L-ribofuranosyl)-1,2,4-triazole-3-carboxamide) is administered to the patient, and wherein the viral infection is an HIV infection, a HCV infection, or a HBV infection.
In one aspect of the inventive subject matter, the administration of the Levovirin(trademark) increases the TH1 response relative to the Th2 response in the patient, and it is especially contemplated that the TH1 response increases on an absolute. In further aspects of the inventive subject matter, Levovirin(trademark) is administered in vivo, preferably injected i.v., or orally taken, wherein the preferred dose of Levovirin(trademark) is between 0.1 mg/kg and 1.0 mg/kg.
Various objects, features, aspects and advantages of the present invention will become more apparent from the following detailed description of preferred embodiments of the invention, along with the accompanying drawings in which like numerals represent like components.